Prof said : ' I am not sure it is such a big problem. Non-specificity in relation to 'disease' pigeonholes does not matter if the feature of interest indicates a sort of mechanism to which one can target a rational treatment. '

Well said.
Our problem is drs have been trying to desperately pigeon hole us with little success and terrible consequences for us in that we fall thru all the cracks. It seems that if we can't be pigeon holed we can't be treated, hence why we feel ignored etc. I wish more medics had your way of thinking!. But as you say above, medicine unfortunately has been commercialized and this doesn't help lateral thinkers gain traction. Not enough fishing expeditions and experimentation. When you think about it , it was only during desperate times of war that medicine made its biggest advances. When ANYTHING was tried with the hope it might work and there weren't "rules" etc.

Reactions to voltaren are not uncommon in anybody and shortness of breath is one of them. Maybe 30-50% of people with RA find taking voltaren regularly pretty hard going. But people with ME may well have more reactions. If ME involves the activation of some sort of protective response mechanism, like production of a cytokine, then it would not perhaps be surprising if that was aggravated by all sorts of things that in other people caused no more than occasionally feeling slightly nauseous or 'mentally blank' as is very common with drugs like voltaren or, in the old days, indomethacin even more so.

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It's a common theme that people with ME tend to be extra-sensitive to a wide range of drugs. I find it useful at times, as it means I can use less, which is cheaper!

@Jill, has your friend tried lower doses of diclofenac (generic name for Voltaren/Voltarol)?

Do you think we might see a protocol for the UK study pertaining to Rituximab/autoimmunity released before the end of 2013? I wondered if there was anything you could tell us about how its all going at UCL?

I would like to ask you what you think how far we are to beat autoimmune diseases. Did we already do a big progress in autoimmunity diseases? Are autoimmune diseases simmilar- so a major discovery in one autoimmune disease could also help other autoimmune diseases or are autoimmune diseases too different? I ask this because of ME perspective. With so few money for ME research I think we need a miracle or a help from the discoveries from other diseases which could bring us further.
I hope my question is not stupid - I am economist

Do you think we might see a protocol for the UK study pertaining to Rituximab/autoimmunity released before the end of 2013? I wondered if there was anything you could tell us about how its all going at UCL?

Thanks

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From my perspective everything is going according to plan at UCL, with various people having done sterling work in getting things started. The slowness of bureaucracy takes its toll but one has to learn to bear with that in this world it seems. It was decided to do a preliminary blood test study on patients who might be suitable for inclusion in a trial, with the hope that this would allow grouping of patients in a way that could make the trial much more informative. That study has been designed and agreed and has gone for administrative approval, to start as soon as approval is available and a research worker has been allocated to the project. A detailed protocol for a trial will then be selected from options that have been considered, in the light of the blood test study. I am afraid I cannot give a useful idea of how long things are going to take but the momentum is there to get on with things as fast as is practical.

I would like to ask you what you think how far we are to beat autoimmune diseases. Did we already do a big progress in autoimmunity diseases? Are autoimmune diseases simmilar- so a major discovery in one autoimmune disease could also help other autoimmune diseases or are autoimmune diseases too different? I ask this because of ME perspective. With so few money for ME research I think we need a miracle or a help from the discoveries from other diseases which could bring us further.
I hope my question is not stupid - I am economist

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Progress in autoimmune disease during my professional lifetime has been enormous. When I first started we had steroids and a few other drugs that did not work very well and were very toxic. We had very little idea how autoimmune processes worked. Now we have a range of drugs which can produce complete remission of symptoms for long periods in many of the autoimmune disorders. We also have a pretty good idea of what is going on. There are still major issues about making treatments safe and practical and trying to get permanent remissions but at least we have a good idea what we should be aiming to do. There are common principles to many autoimmune diseases - so that many of them respond to treatments like rituximab.

The question is a very intelligent one. In fact almost all of the new drugs for autoimmunity were developed for completely different diseases - some of them turn out to work better in autoimmune disease than for what they were designed for! There was no money to develop rituximab for RA. I had to buy the stuff and try it out on my own. So the situation for ME need not be so different - it just needs people to be interested in trying and I think they are beginning to be.

From my perspective everything is going according to plan at UCL, with various people having done sterling work in getting things started. The slowness of bureaucracy takes its toll but one has to learn to bear with that in this world it seems. It was decided to do a preliminary blood test study on patients who might be suitable for inclusion in a trial, with the hope that this would allow grouping of patients in a way that could make the trial much more informative. That study has been designed and agreed and has gone for administrative approval, to start as soon as approval is available and a research worker has been allocated to the project. A detailed protocol for a trial will then be selected from options that have been considered, in the light of the blood test study. I am afraid I cannot give a useful idea of how long things are going to take but the momentum is there to get on with things as fast as is practical.

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Thanks ever so much for the update. Are you able to expand on this blood test? What it is you are looking for perhaps? Totally understand if you can't of course.

Thanks ever so much for the update. Are you able to expand on this blood test? What it is you are looking for perhaps? Totally understand if you can't of course.

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I would prefer not to comment in more detail at this stage. I would normally be happy to describe my own work but I will not be the principal investigator for this work. My role has been to get a collaboration together. I should not be giving a running commentary on other people's efforts. There are also reasons for being cautious about making information available too soon. We may actually want the trial to start without the people treating the patients, or the patients, knowing what the detailed results of the preliminary study are. This may seem odd (some other member of the team or maybe a sealed brown envelope will know) but we need to try very hard to avoid anything that might flavour expectations of results because assessments of fatigue are subjective.

Apologies that I havent kept up with this thread for a few months, but just to add my 2 cents here....I went to a talk recently given by a nutritionist which was specifically about autoimmune illnesses and he discussed several cases of his all of whom responded/improved significantly to treatment which included addressing pathogens, leaky gut, liver detox issues and nutritional deficiencies. Some improved to the extent that they completely lost their original diagnosis, to the surprise of their consultants. Illnesses included RA, Sarcoidosis, Neuromyelitis Optica, MS, SLE.

Drawing Prof Edwards' attention to the 11th IACFS/ME Biennial International Research and Clinical Conference, in case it piques your interest in any way...

Especially this bit:

The 11th IACFS/ME Biennial International Research and Clinical Conference co-sponsored by Stanford UniversityTranslating Science into Clinical Care
20-23 March 2014

Our plenary speaker will be Noel R. Rose, MD, PhD, Director of the Center for Autoimmune Disease Research and a Professor in the Department of Pathology (with joint appointment in the Department of Medicine) at Johns Hopkins University School of Medicine.

He is also a Professor in the W. Henry Feinstone Department of Molecular Microbiology and Immunology at the Johns Hopkins University Bloomberg School of Public health. Dr. Rose's pioneering studies on autoimmune thyroiditis and myocarditis helped to initiate the modern era of research on autoimmune disease. He will address the issue of fatigue and autoimmune disease.

As the H1N1 swine flu pandemic swept the world in 2009, China saw a spike in cases of narcolepsy — a mysterious disorder that involves sudden, uncontrollable sleepiness. Meanwhile, in Europe, around 1 in 15,000 children who were given Pandemrix — a now-defunct flu vaccine that contained fragments of the pandemic virus — also developed narcolepsy, a chronic disease.

Abstract
Narcolepsy, a disorder strongly associated with human leukocyte antigen (HLA)-DQA1*01:02/DQB1*06:02 (DQ0602), is characterized by excessive daytime sleepiness, cataplexy, and rapid eye movement sleep abnormalities. It is caused by the loss of ~70,000 posterior hypothalamic neurons that produce the wake-promoting neuropeptide hypocretin (HCRT) (orexin). We identified two DQ0602-binding HCRT epitopes, HCRT56-68 and HCRT87-99, that activated a subpopulation of CD4(+) T cells in narcolepsy patients but not in DQ0602-positive healthy control subjects. Because of the established association of narcolepsy with the 2009 H1N1 influenza A strain (pH1N1), we administered a seasonal influenza vaccine (containing pH1N1) to patients with narcolepsy and found an increased frequency of circulating HCRT56-68- and HCRT87-99-reactive T cells. We also identified a hemagglutinin (HA) pHA1 epitope specific to the 2009 H1N1 strain, pHA1275-287, with homology to HCRT56-68 and HCRT87-99. In vitro stimulation of narcolepsy CD4(+) T cells with pH1N1 proteins or pHA1275-287 increased the frequency of HCRT56-68- and HCRT87-99-reactive T cells. Our data indicate the presence of CD4(+) T cells that are reactive to HCRT in narcolepsy patients and possible molecular mimicry between HCRT and a similar epitope in influenza pH1N1, pHA1275-287.

Thanks Bob for the pointer to the narcolepsy T cell study. I have been away for a bit and am catching up. I thought I would reply here as it is a general comment of wider relevance.

What intrigues me is that this study provides very plausible evidence for a sort of autoreactivity that probably bears no relation to any of the well known autoimmune diseases. It is a sort of autoreactivity that has often been assumed to occur - T cell based and involving 'cross-reactivity' - but in practice virtually all other autoreactivity (autoimmunity) has only been demonstrated in terms of B cell responses (and no cross -reactivity). A relevant point is that cross-reactivity for B cells (antibody mediated) is not particularly likely to overlap with cross reactivity by T cells since B cells recognise the shape of a whole protein and T cells recognise chopped up peptides.

So if this study can be confirmed this would not just be another autoimmune disease. It would be a completely new sort of disease. (And rituximab would probably have no effect, even if given before damage was done.)

What intrigues me is that this study provides very plausible evidence for a sort of autoreactivity that probably bears no relation to any of the well known autoimmune diseases. It is a sort of autoreactivity that has often been assumed to occur - T cell based and involving 'cross-reactivity' - but in practice virtually all other autoreactivity (autoimmunity) has only been demonstrated in terms of B cell responses (and no cross -reactivity). A relevant point is that cross-reactivity for B cells (antibody mediated) is not particularly likely to overlap with cross reactivity by T cells since B cells recognise the shape of a whole protein and T cells recognise chopped up peptides.

So if this study can be confirmed this would not just be another autoimmune disease. It would be a completely new sort of disease. (And rituximab would probably have no effect, even if given before damage was done.)

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Hypothesising, do you think that T-cell mediated auto-reactivity, involving what you describe as cross-reactivity, could potentially be responsible for auto-immunity that is less localised (e.g. rheumatoid arthritis or asthma), but more generalised/systemic? Or am I barking up the wrong tree?

BTW, Charles Shepherd, of the ME Association says: "There are some interesting causative, clinical and management overlaps between narcolepsy and ME/CFS."

Hypothesising, do you think that T-cell mediated auto-reactivity, involving what you describe as cross-reactivity, could potentially be responsible for auto-immunity that is less localised (e.g. rheumatoid arthritis or asthma), but more generalised/systemic? Or am I barking up the wrong tree?

BTW, Charles Shepherd, of the ME Association says: "There are some interesting causative, clinical and management overlaps between narcolepsy and ME/CFS."

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T cell mediated responses tend to be more local than antibody-mediated ones. T cells will only recognise antigens presented by cells so the reaction will only occur where cells have picked up and preented antigen locally. Antibody mediated responses can involve immune complexes in which the antigen is in the circulation, so the response can be almost anywhere there is blood supply. Antibodies do not tend to get into brain however, except in multiple sclerosis where somehow B cells get into the brain linings (meningeal spaces) or even into brain tissue itself. The more or less silent (non-inflammatory) death of hypocretin producing neurons in the absence of any other events elsewhere would fit very well with a local T cell attack.

I@ jonathan Edwards Would you call an innate reaction to a misfolded cellulair protein autoimmunity?

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No, I think the agreed definition of autoimmunity is an adaptive reaction - i.e. based on acquired mutations in B or T lymphocyte receptors. We all have innate reactions to misfolded self proteins in all cells - which allow the cell to destroy any protein molecules that for some reason have not folded normally.

Yes, I tend to agree. But there may be subtleties. In RA there are HSP60 antibodies but I doubt they cause fatigue in RA - I think that comes from the specific antibodies - rheumatoid factor or anti-citrulline - and TNF release. HSP60 antibodies look to be a bit like the 'smoke with a fire' - an epiphenomenon maybe. As another example, in scleroderma you get more or less the same symptoms from one of three quite different autoantibodies. Everyone with scleroderma has an autoantibody but each person only has one of the three options. So, despite some sceptical remarks from some quarters, I am a believer in each autoimmune ME patient having their own specific autoantibodies (maybe twenty options?) as well as anti-HSP60 smoke. The difficulty with twenty different autoantibodies is that none of them might each show up in enough cases for anyone to take notice, so we may learn more from looking for the smoke at the moment. But I could be wrong.

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I'm sorry if this is dragging up an old point, I've only recently been going through this thread for the comments I have missed. The concept of 20+ autoantibodies being present within the entire potentially autoimmune based ME cohort is something that sounds very interesting and is something I doubt many people have ever considered.

From my reading around the subject it seems clear that there is a definite 'neurological' dysfunction in ME patients and the most common term I see when reading articles around this subject are autonomic dysfunction (which, while an interesting topic is something of an overly broad term) and HPA axis dysfunction (hypothalamic-pituitary-adrenal axis). I admit that much of the discussion regarding this is somewhat beyond me (although I intend to read up on the subject at some point) however it seems an interesting concept, especially given that there could be thousands of unique targets within the hypothalamus and pituitary gland. I'll be interested to see whether the study investigating possible hypothalamus targeted antibodies comes up with anything.

Such dysfunction could go some way to explain the vast array of symptoms patients experience and also the seemingly vast spectrum of morbidity between patients, with some completely bed bound while others are able to struggle on, working full-time. It could also explain why generic test such as blood counts, ESR and CRP are very often normal in patients despite high levels of disability.

That aside, I do have a query regarding the rituximab trial. Are you also recording patients self reported symptoms alongside results from the pre-trial study? It would be interesting to see whether certain symptoms such as swollen lymph nodes, headaches, tremors etc are more or less frequent in a possible responding group - although I doubt this will prove a significant difference I would expect some symptoms to appear more frequently in those who respond. Acute/gradual onset could also have a huge difference although i'm certain these are things you've already considered. I was reading a paper recently exploring how cytokine fluctuations in Lupus appear to correlate to differing symptom complexes (http://www.ncbi.nlm.nih.gov/pubmed/8445045). It's interesting to see the variation that exists even within a fairly well defined disease such as lupus. If ME did truly have numerous different causative autoantibodies perhaps the degree of variation within ME would be even greater.